The present invention relates to a porphyrin compound or a pharmaceutically acceptable salt thereof used for photodynamic diagnosis and/or treatment of animals. The present invention also relates to a photodynamic diagnostic and/or therapeutic agent comprising the porphyrin compound or a pharmaceutically acceptable salt thereof, which is used for photodynamic diagnosis and/or treatment, especially, of tumor in animals.
As a new method of treatment for cancer, photodynamic diagnosis and therapy (PDT: Photodynamic Therapy) has stepped into the limelight. It is a method in which a certain type of porphyrin derivatives is administered to a subject by, for example, intravenous injection to retain the porphyrin derivative in the target cancerous tissues in the subject, followed by laser irradiation to cause selective destruction of the cancerous tissues. The therapy utilizes the two properties of a porphyrin derivative, i.e., selectivity for cancerous tissues and photosensitivity.
The only porphyrin derivative currently used in PDT is porphymer sodium. Porphymer sodium is a mixture compound of 2- to 6-polymer comprising an ether and/or ester of hematoporphyrin derivative. Porphymer sodium is known to cause temporary photosensitivity as an undesirable side effect when administered to human body, and further, selective distribution to cancerous tissues is not sufficient for practical use, and therefore the problem of accumulation in normal tissues is confirmed.
Under the circumstances, a patient treated with porphymer sodium is required to stay in the dark for a long period of time until porphymer sodium is completely excreted from the body so that normal cells are not damaged by the photosensitizing action of porphymer sodium accumulated in normal tissues. However, since porphymer sodium shows a slow excretion rate from normal tissues, it sometimes causes photosensitivity to last for more than six weeks.
In addition, PDT using porphymer sodium has a problem with transmission of the light irradiated by laser through tissues. That is, porphymer sodium has a longest wavelength absorption end at 630 nm and a molar absorption coefficient is as small as 3,000. Since there are many components present in a living body which prevent the transmission of light, such as oxyhemoglobin and water, the light with wavelength of 630 nm exhibits a poor transmission through tissues, which cannot sufficiently reach to deep sites, thus, PDT using porphymer sodium is only intended for cancers developing in the surface layers of 5 to 10 mm depth. The wavelength which is least damaging by the light absorption to the components in a living body is in a range of 650 to 750 nm, therefore, photosensitizers for PDT having the longest wavelength absorption end within such range are most desirable.
Laser devices themselves also have problems. Dye lasers, which are most commonly used at present, have a poor stability in performance and therefore are difficult to handle in practical use. On the other hand, titanium-sapphire lasers enable to facilitate the practice of PDT considerably. However, these types of lasers are limited in the excitable wavelength to not less than 670 nm and not more than 600 nm, and therefore are not applicable to porphymer sodium which has an absorption wavelength of near 630 nm.
Recently, semiconductor lasers (670 nm), which are applicable to compounds exhibiting an absorption near 670 nm, have been developed, and quite recently OPO-YAG laser has been developed, which made it possible to cover almost all visible wavelengths.
As mentioned above, photosensitizers currently used for PDT have various defects and therefore development of new agents without such defects is strongly desired. In an attempt to overcome those problems, a prophyrin compound which is a single compound and exhibits its adsorption in a longer wavelength region (650-800 nm) has been proposed as a second generation agent for PDT.
Examples of such second generation agent includes amino-levulinic acid (ALA) which is a protoporphyrin precursor; asparthyl-chlorin e6 (Np e6) which is a chlorin derivative; benzoporphyrin derivative (BPD) and methatetrahydroxyphenylchlorin (m-THPC), both of which are new type of chlorin derivatives obtained by the structural conversion from hemoglobin-derived porphyrins.
In addition, the present inventors proposed chlorin derivatives and the analogues thereof, e.g., an alkoxyiminochlonyl aspartic acid derivative (Japanese Patent Application Laid-open Nos. 5-97857 and 9-124652), confirming that these compounds are useful as photosensitizers for PDT.
On the contrary, in mammals"" case, suffering from cancer has been a great problem not only in human beings but in animals, especially, in pet animals which are breeding in a house. For treating the cancer of these pet animals, same treatments for human being such as administering anticancer agent or radiotherapy have been performed. Under these circumstances, the present inventors have studied to develop the effective therapeutic methods for treatment of cancer of pet animals and confirmed that among the alkoxyiminochlonyl aspartic acid derivatives, ethoxyiminochlonyl aspartic acid derivatives are useful as photosensitizers for PDT in animals.
Therefore, it is an object of the present invention to provide a porphyrin compound or a pharmaceutically acceptable salt thereof used for photodynamic diagnosis and/or treatment of animal.
Furthermore, it is other object of the present invention to provide a photodynamic diagnostic agent and/or therapeutic agent comprising the porphyrin compound or a pharmaceutically acceptable salt thereof, especially for diagnosis and/or treatment of tumor in animals.
To solve the above-mentioned objects, one aspect of the present invention provides a porphyrin compound represented by the following formula (I): 
wherein Asp represents a residue of aspartic acid, or a pharmaceutically acceptable salt thereof, used for photodynamic diagnosis and/or treatment of animals.
Another aspect of the present invention provides a porphyrin compound represented by the following formula (II): 
wherein Asp represents a residue of aspartic acid, or a pharmaceutically acceptable salt thereof, used for photodynamic diagnosis and/or treatment of animals.
Still another aspect of the present invention provides a photosensitizer for the photodynamic diagnosis and/or treatment containing the porphyrin compound represented by formula (I) or (II) as well as a mixture thereof, or a pharmaceutically acceptable salt thereof.
More specific embodiment of the present invention, it is provided a photosensitizer for the photodynamic diagnosis and/or treatment of tumor of animals containing the porphyrin compound represented by formula (I) or (II), or a pharmaceutically acceptable salt thereof as an active ingredient.